Medications for Treating Alcoholism

Researchers are evaluating medications to assist in treating alcoholism. Such medications may be used to treat withdrawal or co-occurring psychiatric disorders or as an adjunct to psychosocial treatment.

T he prospect of using medications to help treat certain aspects of alcoholism 1 appears increasingly attractive. Two developments have contributed to stimulating research in this area. First, there is an improved understanding of how brain cells use chemical messengers (neurotransmitters) to communicate, thereby producing men tal states and, ultimately, behavior (see sidebar, p. 266). Second, it has been postulated that abnormalities in certain neurotransmitter systems may be common to both alcoholism and depressive disor ders (see the article by Miller,. This suggests that medications effective in treating psychiatric disorders may be useful for treating alcoholism as well. Researchers therefore have a theo retical basis for developing new medica tions as well as further evaluating a large number of existing medications for use in alcoholism treatment. Medications that prove useful in treating aspects of alco holism can serve as adjuncts to standard psychosocial methods of treatment. 1 Throughout this article, terms such as "alcohol abuse," "alcoholism," and "heavy drinking" are used. There is overlap among these terms in the alcoholism literature; therefore, the wording in each case is based on the terms used in the reference cited. After various preliminary studies, the ultimate test of an experimental medica tion is the controlled clinical trial, in which the effects of the medication may be compared with the effects of a medi cally inactive substance (placebo). An additional strategy is the doubleblind trial, in which both subjects and therapists remain ignorant of the treatment adminis tered so that results can be interpreted with minimal bias.
In addition to clinical effectiveness, new medications for treating alcoholism should ideally meet special safety and compliance criteria. Such medications should not • interact harmfully with alcohol • have a significant abuse potential RAYMOND F. ANTON, M. D.,  • be toxic to organs such as the liver, which already may have been damaged by longterm alcohol consumption • have unpleasant side effects that might limit their acceptability with patients whose motivation already may be minimal.
This article briefly discusses medica tions intended to reduce craving, treat psychiatric disorders, discourage con sumption, antagonize alcohol's effects, and ameliorate withdrawal symptoms. (For more detail, see Meyer 1989;Kranzler and Orrok 1989;Litten and Allen 1991;Naranjo and Sellers 1992;Kranzler and Anton in press).

ANTICRAVING MEDICATIONS
Scientists believe that the positively rein forcing effects of alcohol (see sidebar, p. 267) are related to the release of dopa mine into a brain area called the nucleus accumbens (Koob 1992). Dopamine release is controlled by several other neurotrans mitters, including serotonin and the natural ly occurring opiates. Although the specific roles of these neurotransmitters are unclear,

HOW NERVE CELLS COMMUNICATE
The brain is a communication center. Nerve cells in the brain send messages to one another and to other cells in the body, thereby controlling all bodily processes, including thought, emotions, and behavior. Alcohol exerts its effects on mood and behavior by interfering with nerve cell communication. For the most part, the communicating ends of different nerve cells do not touch each other but are separated by a microscop ic gap called a synapse. A nerve cell transmits a message by releasing a chemical called a neurotransmitter into the synapse, to be taken up by the receiving nerve cell. The message receiving surface of a nerve cell is studded with protein molecules called receptors. There are several types of receptors, each of which recognizes and binds to a specific type of neuro transmitter. A given neurotransmitter molecule conforms to its receptor as a key fits into a lock.
The binding of a neurotransmitter to the appropriate receptor sets off a chain of chemical events within the receiving nerve cell. These events ultimately result in the promotion or inhibition of specific functions of that nerve cell.
Any step in the communication process is a potential site of action for psychiatric medications or for drugs, including alcohol, that affect the brain. Medications that mimic or enhance the effects of a neurotransmitter at a recep tor are called agonists. Medications that block or inhibit the normal function of a receptor are called antagonists.
Neurotransmitters of particular importance to alcoholism treatment include dopamine, serotonin, and various opiates. Dopamine is involved in reward and pleasure mechanisms as well as movement coordination. Serotonin modulates the effects of other neurotransmitters; among its many functions are those relating to sleep, aggression, appetite, and mood, including mood disorders. Opiate neurotransmitters are similar to mor phine, codeine, and other natural and synthetic opiates that relieve pain and produce a sensation of pleasure.
-Raymond F. Anton depressant. This medication is relatively safe, has fewer serious side effects than many other antidepressants, and lacks abuse potential (Mendels 1987). In a study of a group of 20 alcoholic men given free access to alcohol in a locked hospital ward for 28 days, fluoxetine lowered alcohol consumption 14 percent during the first week but not subsequently (Gorelick and Paredes 1992). The influ ence of psychosocial factors on these results is unknown. The researchers con cluded that response to medication might vary in different settings. Kranzler and colleagues (in press) found that fluoxetine combined with coping skills therapy did not reduce alcohol relapse and other drinking behavior in outpatient alcoholics. Certain selective serotonin receptor antagonists have decreased alcohol con sumption in preliminary studies (Meert 1993). These medications include on dansetron (Zofran ® ), used to control nau sea and vomiting in patients undergoing cancer chemotherapy, and ritanserin, which has been used to treat anxiety. Ondansetron has been reported to reduce daily alcohol consumption by about 20 percent, compared with placebo, in active ly drinking, nonseverely alcoholdependent patients (Sellers et al. 1994). A large multisite study is examining ritanserin in combination with cognitive behavioral therapy in outpatient alcoholics.
medications that modify their actions may alter the craving for alcohol (table 1).

Opiate Antagonists
The most promising medication for treat ing alcoholism to date is naltrexone (ReVia™), an opiate antagonist. In two studies, naltrexone reduced the relapse rate to heavy alcohol consumption by about 50 percent in alcoholics over a 12week period (Volpicelli et al. 1992;O'Malley et al. 1992); all subjects re ceived additional psychosocial treat ment (see the article by Volpicelli et al.,. Other opiate antagonists also are being examined for effectiveness. For example, a small placebocontrolled study found that nalmefene decreased the rate of relapse to abusive drinking in alcoholics (Mason et al. 1994).

Medications That Affect Serotonin
In addition to its role in brain reward pathways such as the nucleus accumbens (McBride et al. 1991), serotonin may affect the urge to drink indirectly through its role in impulse control and mood stabilization. Serotonin also may alleviate the stress intolerance caused by mood disturbances, thereby reducing the influ ence of environmental experiences on drinking behavior.
A series of studies conducted primarily at the Addiction Research Foundation in Toronto, Canada, examined serotonin enhancing medications in a group of heavy alcohol consumers with minimal alcohol related problems (Naranjo and Bremner 1992). Medications, such as citalopram, zimelidine, and fluoxetine (Prozac ® ), that increase the amount of serotonin at the synapse (see sidebar, p. 266) produced a 10 to 20percent decrease in alcohol consump tion, measured mainly as drinks consumed per day. However, it is unclear whether these medications would be as effective in more severely affected alcoholics.
Although citalopram and zimelidine are not available in the United States, fluoxetine is used widely here as an anti

Medications That Affect Dopamine
Interestingly, few studies have examined the effect on alcoholism of medications that affect the dopamine system directly. One study utilizing the dopamine agonist bromocriptine showed a reduction of craving and alcohol use (Borg 1983). The dopamine antagonist tiapride has shown promise for promoting abstinence in recovering severe alcoholics during the immediate postdetoxification period (Shaw et al. 1994).
Progress in this area has been limited by the significant number of adverse side effects associated with existing medica tions that affect dopamine. Additionally, some medications, such as amphetamine, that stimulate the release of dopamine into the synapse are potentially addictive.

Other Medications
Preliminary results from European studies indicate that calcium homotaurinate re duces alcohol consumption and craving (Lesch et al. 1994;Poldrugo et al. 1994).
The mechanism of this action is unknown but may involve an effect on the brain chemicals glutamate and taurine.

MEDICATIONS TO TREAT ALCOHOLICS WITH PSYCHIATRIC DISORDERS
Comorbidity is the occurrence of two or more illnesses in the same person. Recent largescale population studies have con firmed significant comorbidity of psychi atric disorders and alcohol use disorders (Kessler et al. 1994;Regier et al. 1990; for more information, see the article by Miller,. Researchers are attempting to develop medications to treat psychiatric comorbidity (Anthenelli and Schuckit 1993) on the theory that certain psychiatric conditions may lead to loss of control over alcohol consumption. Although this assumption is controversial, medications under study are generally safe and effective for the psychiatric conditions, and many show promise in animal studies for reducing alcohol con sumption (table 2).

Anxiety Disorders
Many alcoholics display symptoms of excessive or inappropriate anxiety. A commonly prescribed antianxiety medica tion is buspirone (Buspar ® ), which ap pears to exert its effect by raising sero tonin concentrations in the brain. Because an increase in serotonin may lead to a decrease in alcohol consumption (Gorelick and Paredes 1992;Meert 1993), buspirone might be useful for treating alcoholics with comorbidgeneralized anxiety disor ders. In addition, buspirone has no abuse or addiction liability, in contrast to the benzodiazepine tranquilizers (Valium ® and others), which are not recommended for longterm treatment of alcoholics (Malcolm et al. 1992).
Controlled trials of buspirone in anx ious alcoholics have shown inconsistent results. Buspirone decreased both anxiety and alcohol consumption in alcoholic outpatients who also were treated with coping skills therapy (Kranzler et al. 1994). However, buspirone alone may not be effective for alcoholic inpatients, whose anxiety and alcoholism both tend to be more severe than that of alcoholic outpatients (Malcolm et al. 1992).
Panic disorder, a chronic, often debili tating anxiety disorder, is found in a significant subgroup of alcoholics who

REINFORCEMENT AND CRAVING
Research has suggested mechanisms by which alcohol affects brain cells to bring about a state of alcohol depend ence (alcoholism) in susceptible people. For example, the actions of alcohol on certain brain centers may lead to sensations perceived as rewarding, or pleasurable. The process by which a person learns to repeat rewarding behavior is called positive reinforce ment. This process encourages the development of alcoholism in persons who are vulnerable for underlying genetic or psychosocial reasons (Wise and Rompre 1989).
In addition, alcohol tends to relieve stress and anxiety. The process by which a person learns to avoid behavior that causes unpleasant sensations is called negative reinforcement. Some people may have a genetically based or learned stress intolerance (Sher and Levenson 1982) that alcohol amelio rates, leading to negative reinforcement.
The positive and negative reinforc ing effects of alcohol are associated with subjective feelings of craving coupled with a loss of control over alcohol consumption. Craving is not easily defined or quantified because it is a state of mind. Loss of control consists of initiating drinking despite obvious negative consequences or drinking more than is intended. By modifying the links between reward, stress, and craving, medications poten tially could reduce the urge to drink and the loss of control over drinking. As such, this would "tip the balance" so that psychosocial treatments could be more effective.

Depression
Depression may be more common than anxiety in alcoholics. The majority of depressive symptoms in alcoholic patients are alcohol induced and abate shortly after abstinence (Brown and Schuckit 1988). However, a substantial minority of alcoholics suffer from intermittent major depressive episodes, chronic lowgrade depressions, or manicdepressive disorder (see the article by Miller, pp. 261-264). Few studies have examined the treatment of these comorbid conditions. In a preliminary 12week study using imipramine, 45 percent of a group of alcohol abusers and alcoholics with de pressive disorders showed improvement in both mood and drinking behavior. However, these subjects represented only 32 percent of the patients who started the trial, since a number of patients dropped out prior to receiving an adequate dose of medication (Nunes et al. 1993). In a doubleblind trial, the antidepressant desipramine (Norpramin ® ) improved depressive symptoms and reduced drink ing days in depressed alcoholics when compared with a placebo (Mason and Kocsis 1991).
Lithium, prescribed mainly for manic depression, often is used to treat alco holics with mood disorders (Lejoyeux and Ades 1993;Fawcett et al. 1987). During the mid1980's, the Veterans' Admini stration sponsored a large multisite trial of lithium in depressed and nondepressed alcoholics (Dorus et al. 1989). This 12month study of 171 alcoholics with current or past histories of major depres sion or chronic lowgrade depression found no significant effect of lithium on depressive symptoms, alcohol consump tion, or rate of alcohol relapse. As in many of the studies conducted to date, subjects were not required to attend psy chosocial therapy, although almost one half did so for some time during the trial. In addition, manicdepressives were excluded from participating in the trial, and not all depressed patients were de pressed when the study was initiated. Nevertheless, the study suggests that lithium is not useful as a general treat ment for alcoholism in either depressed or nondepressed alcoholics.
Fluoxetine was discussed previously as a potential anticraving medication. Preliminary studies suggest that it might reduce drinking and depressive symptoms in alcoholics with major depression (Cor nelius et al. 1993).

Posttraumatic Stress Disorder
Posttraumatic stress disorder (PTSD) is a poorly understood and complex disorder that often occurs in alcoholics. It has been suggested that the symptoms of PTSD can be accounted for by a deficiency of opiate neurotransmitters (van der Kolk et al. 1989), possibly leading to an increased sensitivity of opiate receptors. Alcohol consumption has been shown to elevate opiate neurotransmitter levels. This sug gests the possibility that persons with PTSD may be more sensitive to alcohol's rewarding or stressreducing effects.
Researchers therefore are investigating the use of naltrexone to normalize opiate receptor sensitivity in these patients.
In addition, because PTSD often is associated with depression, researchers are examining the effect on alcohol con sumption of antidepressants that increase serotonin in the synapse. In combination with these studies, researchers are provid ing patients with psychosocial therapy aimed at PTSD.

AVERSIVE MEDICATIONS
Medications that cause an unpleasant (aversive) reaction when taken with alco hol have long been a mainstay of alco holism treatment. These medications generally interfere with the metabolism of alcohol by the liver, permitting a noxious chemical (acetaldehyde) to accumulate in the blood. Consuming alcohol after taking an aversive medication results in such symptoms as rapid heartbeat, shortness of breath, headache, nausea, and vomiting, thereby discouraging further alcohol consumption (table 3).

Disulfiram
The most widely used and studied aver sive medication is disulfiram (Antabuse ® ). Despite favorable results from preliminary studies, a large, multisite, doubleblind controlled clinical trial conducted by the Veterans' Administration (Fuller et al. 1986) found disulfiram ineffective for maintaining sobriety over an extended period. These negative findings may reflect the failure of many patients to take the medication as prescribed. Those pa tients who consumed alcohol but remained in the study and continued to take their disulfiram significantly decreased their alcohol consumption. Disulfiram may be effective in highly motivated persons who take the medica tion over an extended period of time, especially in situations in which compli ance can be monitored (Chick et al. 1992). In addition, clinicians prescribe disulfiram for shortterm use in patients who have developed some internal control over their craving but who desire addi tional, external protection to face a tem porary highrisk situation.
Some researchers have attempted to develop a longacting disulfiram formula tion that could be injected or incorporated into a timedrelease surgical implant, thereby eliminating the problem of daily medication compliance (Philips 1992). These attempts have not yet been suc cessful. In addition, the safety and patient acceptability of longacting disulfiram formulations have not been clarified (Allen and Litten 1992).

Calcium Carbimide
Calcium carbimide produces an aversive reaction to alcohol similar to that pro duced by disulfiram. In a study by Peachey and colleagues (1989), the 69 alcoholics completing the 4month con trolled study were abstinent on at least 85 percent of the days, and 58 percent re mained abstinent throughout the study. However, the reduction of alcohol con sumption with calcium carbimide was not significantly greater than with placebo. As noted in previous studies, motivation and compliance are thus key factors in evaluating medications taken under con trolled conditions in which support for abstinence is high.

Daidzin
National headlines recently focused on the discovery of a new compound, ex tracted from the ubiquitous southern vine kudzu, that was found to inhibit alcohol consumption by hamsters (Keung and Vallee 1993). This investigation was prompted by the knowledge that kudzu was used in ancient China (600 A.D.) to treat alcohol abuse. However, the com pound's efficacy in treating alcoholism remains to be proven.

ALCOHOL ANTAGONISTS
The concept of medications that would act as "sobering up pills" has captured the interest of clinicians and the public alike. In the emergency room, where intoxicated patients pose a variety of diagnostic and behavioral problems, a medication capa ble of reversing intoxication would be of immense clinical value. An alcohol antag onist also might be used to treat patients who have ingested potentially lethal amounts of alcohol. Unfortunately, exper imental medications capable of antagoniz ing alcohol tend to cause anxiety or promote seizures. Moreover, doses capa ble of causing apparent sobriety may not protect the patient against alcohol's be havioral or medical effects. The patient might still be at risk of driving while impaired or may suffer dangerous adverse health effects through increased drinking in an attempt to overcome the antago nist's effects (Lister and Nutt 1988). Therefore, issues of toxicity and legal liability may limit the development of such medications.
Unlike most other chemicals that affect the brain, alcohol does not have a specific receptor site to which it attaches. Therefore, chemists have been unable to develop an antagonist to directly inhibit or reverse alcohol's actions. However, some medications indirectly antagonize alcohol's effects on certain brain cell functions. The opiate antagonist nalox one, for example, has been reported to reverse the lifethreatening coma caused by very large amounts of alcohol (Sor ensen and Mattisson 1978); this effect has not been replicated.
Theoretically, medications that block alcohol's shortterm effects might be effective over longer periods as well. For example, lithium, at levels used to treat mood disorders, blocks the feeling of intoxication from alcohol doses that produce blood levels at about the level defining legal intoxication in most States (Judd et al. 1977;Judd and Leighton 1984). A similar finding has been report ed for thyrotropinreleasing hormone, a natural substance released from the pitu itary gland that can be taken intravenous ly as a medication. The mechanism of this effect is unknown but may involve a general increase in arousal, counteract ing alcohol's sedative effect (Knutsen et al. 1989).

TREATMENT OF ALCOHOL W ITHDRAWAL
Alcohol withdrawal syndrome occurs in heavy drinkers shortly after cessation of a drinking bout. Symptoms range from profuse sweating, rapid heart beat, elevat ed blood pressure, tremors, agitation, and anxiety to seizures, disorientation, and hallucinations (Gorelick and Wilkins 1986). Medications to treat withdrawal generally modify brain processes, often at receptors. (For more detail, see Castaneda and Cushman 1989;Schultz 1991;Anton and Becker in press.)

Benzodiazepine Sedatives
The most frequently used medications for treating moderate to severe alcohol with drawal are sedatives of the benzodiaze pine class, especially diazepam (Valium) and chlordiazepoxide (Librium ® ). In recent years other medications in this class, such as oxazepam (Serax ® ) and lorazepam (Ativan ® ), also have become widely used for this purpose. The latter medications are particularly useful in pa tients with alcoholicinduced liver damage, who have a diminished ability to metabo lize diazepam and chlordiazepoxide. Benzodiazepines may cause excessive sedation and have some addiction liability. Medications that share some of the effects of benzodiazepines on nerve cells, but which may have less abuse potential be cause of their slightly different chemical structure, are undergoing investigation.

Medications That Affect Norepinephrine
Alcohol withdrawal symptoms appear to result, at least in part, from overactivity of nerve cells that communicate using the neurotransmitter norepinephrine. Therefore, not surprisingly, medications that decrease norepinephrine activity have been found useful in treating alcohol withdrawal. Among these medications are clonidine (Catapres ® ) and propranolol (Inderal ® ), both commonly prescribed to treat high blood pressure. These medica tions do not cause as much mental confu sion or sedation as do benzodiazepines. They also do not induce pleasurable effects that might lead to addiction. In contrast to benzodiazepines, however, clonidine and propranolol do not block the development of seizures, the most serious potential withdrawal symptom (Anton and Becker in press).

Antiseizure Medications
The severity of withdrawal symptoms tends to increase progressively in alco holics who have undergone repeated episodes of withdrawal (Ballenger and Post 1978;Brown et al. 1988;Booth and Blow 1993). This phenomenon may be analogous to a form of brain sensitization called kindling-small electrical currents, individually too small to produce a seizure, will ultimately produce a seizure if applied repeatedly over time. Therefore, medica tions that inhibit kindling have been exam ined for treating alcohol withdrawal. One such medication is carbamazepine (Tegretol ® ), commonly prescribed for epileptic seizures. Carbamazepine has been found in wellcontrolled studies to be as effective as benzodiazepines for treating alcohol withdrawal (Malcolm et al. 1989). It is reasonably safe and lacks abuse liabil ity. More research is needed to determine whether the use of carbamazepine during the first episodes of withdrawal will di minish the risks of more serious symptoms during subsequent withdrawals. Carbama zepine probably is most suited for alco holics who have experienced a previous seizure, irrespective of its relationship to alcohol withdrawal, and for patients who already have had multiple medication assisted detoxifications from alcohol (Brown et al. 1988).

FUTURE DIRECTIONS
Several issues must be addressed in future research on the use of medications to treat alcoholism. Among these is the optimal strategy for combining the use of medica tions with psychosocial treatment. Annis (1991) postulated that alcoholism treat ment targeted toward relapse prevention should proceed in two stages. In the first stage, medication-for example, to reduce craving, increase stress tolerance, or ameliorate a mood disturbance-is com bined with a cognitive social learning therapy intended to strengthen the pa tient's internal controls. If patients attribute their success solely to their medication, they may feel exces sively vulnerable to relapse when the medication is discontinued. Therefore, in the second stage, after craving and mood fluctuations are reduced, cognitive social learning therapy allows the patient to attribute abstinence to selfinitiated behav ioral change, increased coping skills, and enhanced motivation.
Because the concomitant use of medi cations and psychosocial treatment is likely to be more costly than each applied alone, it will be necessary to establish the costeffectiveness for these approaches in the new era of efficient health care deliv ery. Questions regarding the type of training needed to implement these strategies, as well as the length of treatment, will need to be examined during the costbenefit analysis.